More than 700 drugs have failed in stroke clinical trials, an unprecedented rate thought to be attributed to two major factors: 1) most therapeutics focus on a single secondary injury mechanism, and 2) testing in rodent models alone may not be adequate for predicting which treatment is going to be successful. We will combine two unique enabling technologies to address these caveats by using a neural stem cell (NSC) derived biologic product, called NPEX to address multiple secondary injury mechanisms and long-term regenerative affects in an established pig model of ischemic stroke. By expanding on positive data obtained in the mouse model of embolic stroke, we will address both the STAIR and STEPS committee's guidance that a positive outcome should be replicated in a second species and another stroke model. Work from our group and others support that NSC transplants provide benefit when transplanted into rodent or pig brains following stroke. However, transplanted cells are not integrating into host tissue, but providing an immediate paracrine benefit. It is reasonable that these improvements are stimulated by factors provided by the NSC, like small signaling vesicles produced by the cells and released into the local milieu, in the case of ArunA's proprietary NSC's they are called NPEX. The goal of the proposed research is to determine if NPEX provide neuroprotective and/or regenerative benefits after stroke, in an established pig model of stroke that shares many important physiological characteristics with humans. These include having a more evolutionarily complex, larger gyrencephalic brain, and similar gray and white matter composition to the human brain. These similarities make the porcine model an excellent secondary stroke model, allowing ArunA to expedite the proof of concept studies required to assess the therapeutic potential of NPEX following human stroke. The nanometer scale size of NPEX is a huge advantage over traditional cell therapies because they can be continuously produced in large quantities, from cells manufactured in a relatively small footprint, using a streamlined process that has already supported 12 years of commercial cell manufacturing. NPEX can be produced as an off the shelf product that can be thawed and injected intravenously or into cerebral spinal fluid directly, and can be administered in multiple doses, as opposed to NSC therapy, thus supporting the recovery of the injured brain over time as opposed to a bolus following cell injection. ArunA's ability to pursue phase II funding and commercial investment is more attainable by addressing proof of concept studies that tackle known impediments in the early stages of product development. Toward this goal, ArunA has engaged Biologics Inc. (see letter) to develop a gap analysis and roadmap to IND filing as well as clinical trials. Success in the pig stroke model positions ArunA as the only entity able to produce NPEX at a scale facilitating large animal studies, and provides crucial information needed to proceed to the next IND-enabling studies.
Public Health Relevance Statement: Project Narrative The goal of the proposed research is to determine if neural stem cell derived signaling vesicles, called NPEX, provide neuroprotective and/or regenerative benefits following stroke. These characteristics will be evaluated in an established pig model of stroke that shares many important neurophysiological similarities with humans, providing a clear assessment of therapeutic potential for human stroke. These proof of concept studies will help ArunA Biomedical establish a path for regulatory discussions with the FDA and secure commercial investment for production of exosome therapeutics on a commercial scale.
Project Terms: Affect; Anatomy Qualifier; Anatomical Sciences; Anatomic structures; Anatomic Structures and Systems; Anatomic Structure, System, or Substance; Anatomic Sites; Anatomic; Anatomy; Animals; Engineering / Architecture; Architecture; astrocytic glia; Astroglia; Astrocytus; Astrocytes; Biologic Assays; Bioassay; Assay; Biological Assay; biotherapeutic agent; biopharmaceutical; Biological Agent; Biologic Products; Biological Products; biotherapy; biotherapeutics; biological treatment; biological therapeutic; Biological Therapy; Biologic Therapy; Biological Response Modifier Therapy; Encephalon; Brain Nervous System; Brain; cultured cell line; Strains Cell Lines; CellLine; Cell Line; Cell Viability; Cell Survival; Cell Body; Cells; spinal fluid; cerebral spinal fluid; Cerebrospinal Fluid; cerebrovascular blood flow; cerebrocirculation; cerebral circulation; cerebral blood flow; brain blood flow; Cerebrovascular Circulation; Clinical Trials; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Pharmaceutical Preparations; Gait; Goals; substantia grisea; gray matter; Modern Man; Human; Industry; Infarction; infarct; Injection of therapeutic agent; Injections; Investments; Magnetic Resonance Imaging; Zeugmatography; Nuclear Magnetic Resonance Imaging; NMR Tomography; NMR Imaging; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MRI; MR Tomography; MR Imaging; Metabolism; Metabolic Processes; Intermediary Metabolism; Mus; Murine; Mice Mammals; Mice; Neurons; neuronal; Neurocyte; Neural Cell; Nerve Unit; Nerve Cells; neurophysiology; neurophysiological; Oligodendroglia; Oligodendroglia Cell; Oligodendrocytus; Oligodendrocytes; Drug Kinetics; Pharmacokinetics; Physiology; Alteplase; t-PA; Tissue-Type Plasminogen Activator; Tissue Plasminogen Activator; Tissue Activator D-44; T-Plasminogen Activator; Recombinant Tissue Plasminogen Activator; Play; Production; Proteins; Publishing; Rattus; Rats Mammals; Rat; Common Rat Strains; Recommendation; Natural regeneration; regenerate; Regeneration; Research; Rodent; Rodents Mammals; Rodentia; Role; social role; Signal Transduction; biological signal transduction; Signaling; Signal Transduction Systems; Intracellular Communication and Signaling; Cell Signaling; Cell Communication and Signaling; Stem cells; Progenitor Cells; stroke; cerebrovascular accident; cerebral vascular accident; brain attack; Cerebrovascular Stroke; Cerebrovascular Apoplexy; Cerebral Stroke; Brain Vascular Accident; Apoplexy; Family suidae; suid; porcine; Swine; Suidae; Pigs; Miniature Swine; miniswine; mini-swine; mini pig; Minipigs; Technology; Testing; Time; Tissues; Body Tissues; Toxicology; transplant; Transplantation; Universities; Work; Injectable; Blinded; Injury; improved; Area; Phase; Biological; Physiologic; Physiological; Cell Transplants; Chemicals; Lesion; Recovery; Funding; brain-injured; brain damage; Acquired brain injury; Brain Injuries; Letters; Immune response; immunoresponse; host response; Immunological response; Engraftment; Cell Therapy; cell-based therapy; Therapeutic; Vesicle; Intravenous; Complex; protein profiling; Sensory; Source; cell type; meetings; experience; Membrane; membrane structure; paracrine; success; Animal Model; model organism; model of animal; Animal Models and Related Studies; knowledge base; knowledgebase; relating to nervous system; neural; white matter; substantia alba; Positioning Attribute; Position; neurogenesis; Modeling; Property; response; Pluripotent Stem Cells; stroke therapy; Proteomics; Ischemic Stroke; nerve stem cell; neuroprogenitor; neuronal stem cells; neuronal progenitor cells; neuronal progenitor; neuron progenitors; neural progenitor cells; neural progenitor; neural precursor; Neural Stem Cell; Inflammatory Response; Address; Dose; Bolus Infusion; Bolus; Data; Human Pathology; Mesenchymal; Motor; Rodent Model; Small Business Innovation Research; SBIR; Small Business Innovation Research Grant; Monitor; Characteristics; Molecular; Process; sex; Behavioral; preclinical; pre-clinical; nanometer sized; nanometer scale; nano scale; nano meter sized; nano meter scale; nanoscale; imaging spectroscopy; spectroscopic imaging; Outcome; aged; mouse model; murine model; functional improvement; function improvement; FDA approved; Biological Markers; biomarker; biologic marker; bio-markers; regenerative; product development; Secure; transcriptome sequencing; RNAseq; RNA sequencing; RNA Seq; microvesicles; exosome; extracellular vesicles; stroke treatment; treating stroke
